CN101229124A - Ivermectin polylactic acid nano particle antibiotic medicine and preparing method thereof - Google Patents
Ivermectin polylactic acid nano particle antibiotic medicine and preparing method thereof Download PDFInfo
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- CN101229124A CN101229124A CNA2008100174898A CN200810017489A CN101229124A CN 101229124 A CN101229124 A CN 101229124A CN A2008100174898 A CNA2008100174898 A CN A2008100174898A CN 200810017489 A CN200810017489 A CN 200810017489A CN 101229124 A CN101229124 A CN 101229124A
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Abstract
The invention discloses an antibiotic drugs of Cu-PLA--NP is between 10 to 100nm, the percentage between materials and qualities are as follow: ivermectin 5 percent to 20 percent, polylactic acid 20 percent to 25 percent, surfactants 45 percent to 58 percent, acetone 3.5 percent to 6 percent, ethanol 3.5 percent to 6 percent, and the rest is distilled water, the sum of the quality percentage of the above materials is 100 percent, the ivermectin polylactic acid nano-grain can not only keep the characteristics of ivermectin such as the broad spectrum, the high effect, the low side effect, and the high safety, but also overcome the shortcomings of ivermectin such as the short acting time, so as to reach the releasing effect of drugs, be convenient for medication and be safe and effective.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of novel form of antibiotic medicine ivermectin, particularly antibiotic medicine of a kind of ivermectin polylactic acid nano particle and preparation method thereof.
Background technology
Ivermectin Ivermectin is the semi-synthetic Macrolide multicomponent antibiotic that produces from soil microorganism A Foman streptomycete (Streptomycesavermitilis) fermentation.Be the parasiticide antibiotic of a kind of novel, efficient, wide spectrum, safety, multiple endoparasite and ectoparasite had good repelling and killing efficacy, and do not have cross resistance with other antiparasitic, veterinary clinic extensive use at home and abroad.Ivermectin all has effect to most of nematicide (but non-all nematicides) of various life cycle; Microfilariae of ohchocerciasis to filaria volvulus is effective, but invalid to adult; Also effective to the excrement strongylid that only is in intestinal.Ivermectin has optionally inhibitory action, by with no spinal animals neurocyte and muscle cell in glutamic acid be that the high-affinity of the chloride channel of valve combines, thereby cause the increase of cell membrane to the chloride ion permeability, cause neurocyte or muscle cell hyperpolarization, make parasite paralysis or dead.This medicine also can interact with the chloride channel of other part valve (as neurotransmitter g-aminobutyric acid (GABA)).The selectivity of this medicine is because do not have glutamic acid-chloride channel in some mammalian bodies, and ivermectin only has low-affinity to mammal part-chloride channel.Ivermectin can not penetrate people's blood brain barrier, and domestic animal is had higher safety.To endoparasite and ectoparasite particularly some nematicide (roundworm) class and arthropod class have the good effect of killing, but invalid to cestode, trematodiasis and protozoacide.
At present, the ivermectin that circulates on the market (IVM) mostly is ordinary preparation, and each administration weak point of holding time needs multiple dosing, has the shortcoming of using inconvenience, expending a large amount of manpower and materials.Therefore, exploitation long-acting controlled release preparation is the desirability of animal husbandry development.
Summary of the invention
At the shortcoming of above-mentioned prior art with not enough, the object of the present invention is to provide a kind ofly be evenly distributed, transparent, good stability, side effect are little, the antibiotic medicine of ivermectin polylactic acid nano particle with slow releasing function.
The technical scheme that realizes the foregoing invention purpose is: a kind of ivermectin polylactic acid nano particle antibiotic medicine, this nano emulsion composition particle diameter is between 10～100nm, its raw material and mass percent thereof are: ivermectin 5%～20%, polylactic acid 20%～25%, surfactant 45%～58%, acetone 3.5%～6%, ethanol 3.5%～6%, surplus is a distilled water, and the mass percent sum of above-mentioned raw materials is 100%.
Described surfactant is any one among poloxamer (F68), Tween80 and the Span80.
The present invention is that using emulsion-solvent evaporated method prepares ivermectin polylactic acid nano particle, and it is particularly extremely important that the selection of surfactant just seems.The HLB value of surfactant is big more, and the nanoparticle particle diameter of preparation is more little; The power of the hydrophilic ability of HLB size decision table surface-active agent, the surfactant that hydrophilic is stronger can not only make organic facies be dispersed in aqueous phase, but also plays solubilization, improves the stability of dispersion in WATER AS FLOW MEDIUM, stoped the gathering of polymer, the nanoparticle particle diameter is reduced; The used surfactant of medicinal nano grain also requires energy biodegradation, hypotoxicity and nonirritant; So the surfactant that the present invention selects for use is low toxicity, non-stimulated, non-ionic surface active agent poloxamer (F68), Tween80 and Span80 that HLB is bigger.
Another object of the present invention has provided a kind of preparation method of antibiotic medicine of ivermectin polylactic acid nano particle, specifically may further comprise the steps:
1) accurately takes by weighing each raw material: ivermectin, polylactic acid, acetone, ethanol, water, surfactant;
2) the second alcohol and water is mixed and stir;
3) ivermectin is joined in the acetone soln that is dissolved with polylactic acid, fully dissolving;
4) the more above-mentioned drips of solution that is dissolved with ivermectin is added in the second alcohol and water that has stirred, stirs while dripping.
5) 50 ℃ of distilling under reduced pressure steam organic solvent, obtain having the antibiotic medicine of light blue opalescent ivermectin polylactic acid nano particle.
PLA controls the release of medicine as sustained-release matrix, and its advantage has: (1) polymer is nontoxic, non-stimulated; (2) by the requirement of medicine, its degradation speed of may command; (3) can finally be formed water and carbon dioxide by biological decomposition and absorption.(4) intensity height, plasticity is strong.
Ivermectin is the parasiticide antibiotic of a kind of novel, efficient, wide spectrum, safety, and the weak point but the each administration of the dosage form on the market is held time needs multiple dosing.The present invention discharges drug slow with the carrier of polylactic acid nano particle as ivermectin, reduces administration number of times.
The antibiotic medicine of ivermectin polylactic acid nano particle of the present invention compared with prior art has the following advantages:
1. the antibiotic medicine particle diameter 10nm～100nm of ivermectin polylactic acid nano particle of the present invention is that ivermectin is dissolved in organic facies, adds water again and stirs, and self emulsifying forms nano-particle.Preparation is simple, power consumption is low, do not need just energy mass production of special installation.
2. ivermectin polylactic acid nano particle of the present invention is evenly distributed, transparent, good stability, is easy to absorption, the utilization of body to medicine.
3. ivermectin polylactic acid nano particle of the present invention has the slow release effect, can keep long administration time, need not multiple dosing, reduces amount of drug and medication number of times.Use convenience, save a large amount of manpower and materials.
4. ivermectin polylactic acid nano particle preparation method of the present invention is simple, power consumption is low, do not need just energy mass production of special installation.
Specific implementation method
Below in conjunction with the inventor provide embodiment, the experiment example illustrate.
Embodiment 1 contains the polylactic acid nano particle of 5% ivermectin
This ivermectin polylactic acid nano particle has by weight percentage: 5% ivermectin, 20% polylactic acid, 5.5% acetone, 55% surfactant and all the other are second alcohol and water (ethanol: water=1: 3).Ivermectin is joined in the acetone soln that is dissolved with polylactic acid, fully dissolving; Again the above-mentioned drips of solution that is dissolved with ivermectin is added in the second alcohol and water that has stirred, stirs while dripping; Distilling under reduced pressure steams organic solvent, obtains containing the polylactic acid nano particle of 5% ivermectin.
Embodiment 2, contain the polylactic acid nano particle of 8% ivermectin
This ivermectin polylactic acid nano particle has by weight percentage: 8% ivermectin, 20% polylactic acid, 6% acetone, 56% surfactant, all the other are second alcohol and water (ethanol: water=1: 2).Ivermectin is joined in the acetone soln that is dissolved with polylactic acid, fully dissolving; Again the above-mentioned drips of solution that is dissolved with ivermectin is added in the second alcohol and water that has stirred, stirs while dripping; Distilling under reduced pressure steams organic solvent, obtains containing the polylactic acid nano particle of 8% ivermectin.
Embodiment 3, contain the polylactic acid nano particle of 10% ivermectin
This ivermectin polylactic acid nano particle has by weight percentage: 10% ivermectin, 20.5% polylactic acid, 6% acetone, 57% surfactant, all the other are second alcohol and water (ethanol: water=1: 1).Ivermectin is joined in the acetone soln that is dissolved with polylactic acid, fully dissolving; Again the above-mentioned drips of solution that is dissolved with ivermectin is added in the second alcohol and water that has stirred, stirs while dripping; Distilling under reduced pressure steams organic solvent, obtains containing the polylactic acid nano particle of 10% ivermectin.
Embodiment 4, contain the polylactic acid nano particle of 15% ivermectin
This ivermectin polylactic acid nano particle has by weight percentage: 15% ivermectin, 21% polylactic acid, 5.5% acetone, 58% surfactant, all the other are second alcohol and water (ethanol: water=1: 1).Ivermectin is joined in the acetone soln that is dissolved with polylactic acid, fully dissolving; Again the above-mentioned drips of solution that is dissolved with ivermectin is added in the second alcohol and water that has stirred, stirs while dripping; Distilling under reduced pressure steams organic solvent, obtains containing the polylactic acid nano particle of 10% ivermectin.
Embodiment 5, contain the polylactic acid nano particle of 20% ivermectin
This ivermectin polylactic acid nano particle has by weight percentage: 20% ivermectin, 21% polylactic acid, 5.5% acetone, 55% surfactant, all the other are second alcohol and water (ethanol: water=1: 1).Ivermectin is joined in the acetone soln that is dissolved with polylactic acid, fully dissolving; Again the above-mentioned drips of solution that is dissolved with ivermectin is added in the second alcohol and water that has stirred, stirs while dripping; Distilling under reduced pressure steams organic solvent, obtains containing the polylactic acid nano particle of 10% ivermectin.
Embodiment 6
Ivermectin 5%, polylactic acid 20%, surfactant 58%, acetone 3.5%, ethanol 3.5%, 10% distilled water.
Embodiment 7
Ivermectin 20%, polylactic acid 20%, surfactant 45%, acetone 4%, ethanol 4%, 7% distilled water.
Embodiment 8
Ivermectin 15%, polylactic acid 22%, surfactant 50%, acetone 3.5%, ethanol 3.5%, 6% distilled water.
The particle diameter and the stable determination experiment of the polylactic acid nano particle of test example 1 ivermectin of the present invention
1. the polylactic acid nano particle with ivermectin of the present invention detects in Xibei Univ. of Agricultural ﹠ Forest Science ﹠ Technology electron microscope experiment chamber, and the result shows that its particle diameter between 10～100nm, is uniformly dispersed form stable.See Fig. 1.
2. the mensuration of the antibiotic medicine of ivermectin polylactic acid nano particle is to see its stability by light stability test, temperature stability test, sees whether it has layering, muddiness and crystal to separate out.
1) light stability test
The antibiotic medicine of the ivermectin polylactic acid nano particle for preparing is in right amount packed in the vial, and sealing places under the illumination, and light at room temperature is according to 10d, in 1d, 3d, 5d, 7d, 10d sampling.The result shows that the antibiotic medicine of ivermectin polylactic acid nano particle still keeps clear, does not have muddy, lamination.
2) temperature stability test
The antibiotic medicine of the ivermectin polylactic acid nano particle for preparing is in right amount packed in the vial, sealing, placing keeps sample under 4 ℃ of refrigerators, 25 ℃ and 37 ℃ three kinds of temperature conditions of room temperature investigates 30d, observes every the 5d sampling.The result shows that the antibiotic medicine of this ivermectin polylactic acid nano particle all keeps clear under these three kinds of temperature conditions, does not see the phenomenon of layering, muddiness, and temperature stability is good.
Test example 2, blood drug level analysis experiment
Laboratory animal is a sheep, by 50 kg body weight subcutaneous injection examples, 5 preparation 1.5ml, is contrast with commercially available conventional ejection preparation, regularly takes to test the Sanguis caprae seu ovis sample, measures ivermectin concentrations in the blood plasma, and assay method is fluorescence-high pressure lipuid chromatography (HPLC).Experimental result such as following table:
The polylactic acid nano particle blood drug level analysis experiment of table 1 5% ivermectin
| Sample time (d) | 1 | 2 | 3 | 5 | 7 | 10 | 35 |
| Ivermectin nano particle preparations blood drug level (ng/ml) | 6 | 11 | 15 | 17 | 24 | 16 | 10 |
Table 2 5% ivermectin injection blood drug level analysis experiment
| Sample time (h) | 1 | 2 | 5 | 8 | 11 | 24 | 48 |
| The ivermectin ejection preparation | 12 | 24 | 31 | 21 | 15 | 11 | 5 |
| Blood drug level (ng/ml) |
From above-mentioned experimental result, the conventional injection of ivermectin 2～8h blood drug level after administration peaks, and almost disappears behind the 48h; And ivermectin polylactic acid nano particle injection 5～10d blood drug level after administration just peaks, and fades away behind the 35d.Show that the prepared ivermectin polylactic acid nanometer of the present invention has tangible slow release effect.
The drug effect contrast experiment of the polylactic acid nano particle of test example 3, common ivermectin preparation (Ivomec) and ivermectin
1. grouping
Select to infect the sick rabbit of itch mite or acaricide, be divided into four groups at random, every group 12, be respectively matched group, common ivermectin preparation (Ivomec picks up the ivermectin injection of g/L) group, 5% ivermectin polylactic acid nano particle group and 10% ivermectin polylactic acid nano particle group.
2. administration
Ivermectin ordinary preparation group is pressed 0.5mg/kg body weight dosage subcutaneous injection Ivomec, and 14d is with dosage repeat administration 1 time.5% ivermectin polylactic acid nano particle group and 10% ivermectin polylactic acid nano particle group are pressed ivermectin 1.0mg/kg and 5.0mg/kg body weight single dose subcutaneous injection ivermectin microsphere suspensoid respectively.
3. pathological changes is observed and is kept the score
1) ear's lesion score method
0-be no any pathological changes, there is not the demodicid mite of living;
1-for only in one's ear, there is pathological changes in basal part of the ear portion and the demodicid mite that lives;
2-for pathological changes begins to see auditory meatus, auditory meatus has secretions;
3-involve whole auditory meatus gill outer rim for pathological changes;
4-involve position beyond the auditory meatus for pathological changes.
2) lesion score method due to the acaricide
0-be no pruritus, no crust skin;
1-for pruritus, no crust skin are arranged;
2-for pruritus is arranged, crust is confined to claw or nose;
3-be that pruritus is serious, crust is thicker, and vola and nose diseased region area are bigger;
4-be that crust is thick, pathological changes involves whole body.
4. the comprehensive scoring system of sick rabbit
Only infect itch mite or the acaricide person keeps the score with infected acaricide, mixed infection person is to keep the score than the severe infections acaricide.
5. the demodicid mite that lives is checked
Inspection itching in the ear demodicid mite is directly got external auditory meatus secretions, when checking acaricide, scrapes the scurf of getting the crust edge with blade.Pathological material of disease is soaked into normal saline, and microscopically is observed.The demodicid mite that lives checks after the administration same day and administration the 7th, 14,28d respectively carries out 1 time.
6. general clinicing symptom observation
Regularly the test rabbit is weighed before the administration and after the administration, and the active situation of viewing test rabbit and have or not symptom such as pruritus.Dead rabbit is analysed, with preliminary definite cause of death.
7. curative effect is judged
With crust loose or dislocation after the administration, heal and begin to grow virgin wool in the position of festering, and it is effective for treatment that the microscopy pathological material of disease does not have demodicid mite alive.
8. result
1) symptom and the pathological changes of sick rabbit before the administration
This test selected sick rabbit clinical symptoms and pathological changes all more obvious, all be typical itching in the ear demodicid mite or acaricide infection symptoms before the administration; The psoroptic acariasis rabbit mostly is pathological changes and has spread to whole external auditory meatus, volume secretions is arranged in the auditory meatus and dry up into crust, and two ears are sagging, often get rid of a symptom.It is the most obvious with extremity and nose pathological changes that the acaricide rabbit becomes, and crust is thicker, and it is many more than 1cm to merge the focus diameter, and has hemorrhage even skin ulceration, and pruritus is serious.Some sick rabbits are itch mite and acaricide mixed infection, and indivedual sick rabbit symptoms and pathological changes are serious, and whole body all has crust.
2) demodicid mite that lives detects the demodicid mite check results of living before and after 4 groups of test rabbit administrations and sees Table 2.
Demodicid mite check result alive before and after table 2 administration
| Group | The demodicid mite that lives before the administration detects ratio | After the administration 7 days | After the administration 14 days | After the administration 28 days | ||||
| Itch mite | Acaricide | Itch mite | Acaricide | Itch mite | Acaricide | Itch mite | Acaricide | |
| Matched group Ivomec group 5% ivermectin polylactic acid nano particle group 10% ivermectin polylactic acid nano particle | 7/12 8/12 9/12 7/12 | 5/12 4/12 5/12 6/12 | 7/10 1/12 0/11 0/11 | 4/10 2/12 0/11 0/11 | 6/9 2/12 0/11 0/11 | 4/9 1/12 0/11 0/11 | 5/8 1/12 0/11 0/11 | 4/8 0/12 0/11 0/11 |
3) clinical symptoms change of the sick rabbit of duration of test
The matched group rabbit is dead 2,1 and 1 respectively of the 1st, 2 and 4 weeks in the process of the test; 5% ivermectin polylactic acid nano particle group and 10% ivermectin polylactic acid nano particle group are also each dead 1 of the 1st week.Dead rabbit is the pathological changes severe patient, and especially the itching in the ear mite infestationss are particularly serious, and occur epileptic nervous symptoms person before death.2-3d after the administration, the treatment rabbit shows the pruritus aggravation, and pruritus weakens gradually afterwards, to there not being symptoms such as obviously getting rid of head, the foot that bites the 2nd week.The matched group rabbit then gets rid of pruritus symptom aggravations such as head, the foot that bites.
4) pathological changes and lesion score
Respectively organize rabbit change comprehensive grading before the administration and mostly be 2 or 3, indivedual rabbits are 4.After the administration, Ivomec group and ivermectin nanoparticle group rabbit mainly show as demodicid mite recall rate alive and obviously descend in the visible obvious curative effects of 7d, auditory meatus crust loose or dislocation, the auditory meatus endocrine reduces, extremity (main claw) and nose decrustation, and the ulcer kitchen range begins healing.During 14d, the large tracts of land decrustation, the position of festering begins to grow new granulation tissue, and the edge grows virgin wool.During Ivomec group 14d, the demodicid mite recall rate of living is higher, so carry out drug treatment the 2nd time.To 28d, treatment is organized most rabbit crusts and is come off fully, and focus heals substantially, and grows virgin wool, and most rabbits do not detect demodicid mite alive.Slightly variant between each group of pathological changes comprehensive grading, the matched group pathological changes is not seen improvement.
Claims (2)
1. ivermectin polylactic acid nano particle antibiotic medicine, it is characterized in that, this nano emulsion composition particle diameter is between 10～100nm, its raw material and mass percent thereof are: ivermectin 5%～20%, polylactic acid 20%～25%, surfactant 45%～58%, acetone 3.5%～6%, ethanol 3.5%～6%, surplus is a distilled water, and the mass percent sum of above-mentioned raw materials is 100%;
Described surfactant is any one among poloxamer F68, Tween80 and the Span80.
2. prepare the preparation method of the antibiotic medicine of the described ivermectin polylactic acid nano particle of claim 1, it comprises the following steps:
1) accurately takes by weighing each raw material: ivermectin, polylactic acid, acetone, ethanol, water, surfactant;
2) the second alcohol and water is mixed and stir;
3) ivermectin is joined in the acetone soln that is dissolved with polylactic acid, make it to dissolve fully;
4) the more above-mentioned drips of solution that is dissolved with ivermectin is added in the second alcohol and water that has stirred, stirs while dripping;
5) 50 ℃ of distilling under reduced pressure steam organic solvent, obtain having the antibiotic medicine of light blue opalescent ivermectin polylactic acid nano particle.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109223949A (en) * | 2018-11-27 | 2019-01-18 | 昆明市中医医院 | The preparation method of Sanguis Draxonis flavoniod nanoparticle |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109223949A (en) * | 2018-11-27 | 2019-01-18 | 昆明市中医医院 | The preparation method of Sanguis Draxonis flavoniod nanoparticle |
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